Inhibitory Role of Peroxisome Proliferator-Activated Receptor Gamma in Hepatocarcinogenesis in Mice and In Vitro

Although peroxisome proliferator-activated receptor gamma (PPAR gamma) agonist have been shown to inhibit hepatocellular carcinoma (HCC) development, the role of PPAR gamma in hepatocarcinogenesis remains unclear. We investigated the therapeutic efficacy of PPAR gamma against HCC. PPAR gamma-deficient (PPAR gamma(+/-)) and wild-type (PPAR gamma(+/+)) littermates were used in a diethylnitrosamine (DEN)-induced HCC model and treated with PPAR gamma agonist (rosiglitazone) or the vehicle alone for 8 months. The effects of PPAR gamma on HCC cell growth and apoptosis were examined using PPAR gamma-expressing adenovirus (Ad-PPAR gamma). PPAR gamma(+/-) mice were more susceptible to DEN-induced HCC than PPAR gamma(+/+) mice (94% versus 62%, P < 0.05), and rosiglitazone significantly reduced the incidence of HCC in PPAR gamma(+/+) mice (vehicle 62% versus treatment 24%, P < 0.01), but not in PPAR gamma(+/-) mice, indicating that PPAR gamma suppresses hepatocellular carcinogenesis. A pronounced expression of PPAR gamma was observed in a HCC cell line (Hep3B) infected with Ad-PPAR gamma. Such induction markedly suppressed HCC cell viability (P < 0.01). Further, Hep3B infection with Ad-PPAR gamma revealed a decreased proportion of cells in S-phase (12.92% versus 11.58%, P < 0.05), with arrest at G(2)/M phase (38.2% versus 55.68%, P < 0.001), and there was concomitant phosphorylation of the key G(2)/M phase inhibitors cdc25C and cdc2. PPAR gamma overexpression increased cell apoptosis (21.47% versus 35.02%, P < 0.01), mediated by both extrinsic (Fas and tumor necrosis factor-alpha) and intrinsic (caspase-9, caspase-3, caspase-7, and poly[ADP-ribose] polymerase) pathways. Moreover, PPAR gamma directly induced a putative tumor suppressor gene, growth differentiation factor-15. Conclusion: Loss of one PPAR gamma allele is sufficient to enhance susceptibility to HCC. PPAR gamma suppresses tumor cell growth through reducing cell proliferation and inducing G(2)/M phase arrest, apoptosis, and up-regulating growth differentiation factor-15. Thus, PPAR gamma acts as a tumor-suppressor gene in the liver. (HEPATOLOGY 2010;51:2008-2019)